Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive, fatal degenerative disorder mainly, but not exclusively, affecting motor neurons. The disease is characterized by progressive muscle weakness, atrophy and spasticity. Currently, no cure for ALS is available. Most patients suffer from the sporadic form of this disease, while approximately 10% have familial ALS. Mutations in several genes are known to cause this hereditary form. Mutations in superoxide dismutase 1 (SOD1), TAR-DNA binding protein (TARDBP) and fused in sarcoma/translated in liposarcoma (FUS/TLS), and hexanucleotide repeat expansions in C9orf72 are the most prevalent.1-5 
Due to the word “sclerosis” (literally: “hardening”) in the name, it is sometimes confused with multiple sclerosis, although they are very distinct neurological diseases. Multiple sclerosis (MS) is an inflammatory disease of white matter, primarily damaging myelin sheets of neurons. MS affects more women than men, may lead to changes in sensation (hypoesthesia), visual problems and cognitive impairment, and life expectancy for most patients exceeds 20 years.
ALS on the other hand is a grey matter disease caused by the degeneration of neurons located in the anterior horn of the spinal cord and the cortical neurons that provide their afferent input. Sensory function generally is spared, as is cognitive function and oculomotor activity. Most people with ALS die from respiratory failure, usually within three to five years from the onset of symptoms.
Although survival of ALS patients is only three to five years on average, variability of disease duration is quite large, ranging from only a few months to several decades. Even survival of patients with the same mutation in the same gene in the same family is very variable.6, 7 Similarly, age of onset can range from second to ninth decade of life.8 Genetic factors are expected to explain this variability by modifying the phenotype, both in sporadic and familial ALS. The identification of these modifying pathways is of interest, as they are likely to reveal novel targets for intervention. Small animal models, such as flies, worms and zebrafish, are very useful for genetic and compound screening.9-12 To this end, zebrafish models for ALS were previously developed. Overexpressing mutant SOD1 or TDP-43 in zebrafish embryos induces a motor axonopathy, characterized by shorter and aberrantly branched motor axons.13, 14 The identification of the factors underlying variability is of interest, as they may represent targets for therapeutic intervention.